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Prognosis Factors in Probands with an FBN1 Mutation Diagnosed Before the Age of 1 Year 0031-3998/11/6903-0265 Vol. 69, No. 3, 2011 PEDIATRIC RESEARCH Printed in U.S.A. Copyright © 2011 International Pediatric Research Foundation, Inc. Prognosis Factors in Probands With an FBN1 Mutation Diagnosed Before the Age of 1 Year CHANTAL STHENEUR, LAURENCE FAIVRE, GWENAE¨ LLE COLLOD-BE´ ROUD, ELODIE GAUTIER, CHRISTINE BINQUET, CLAIRE BONITHON-KOPP, MIREILLE CLAUSTRES, ANNE H. CHILD, ELOISA ARBUSTINI, LESLEY C. ADE` S, UTA FRANCKE, KARIN MAYER, MINE ARSLAN-KIRCHNER, ANNE DE PAEPE, BERTRAND CHEVALLIER, DAMIEN BONNET, GUILLAUME JONDEAU, AND CATHERINE BOILEAU Service de Pe´diatrie [C.S., B.C.], Hoˆpital Ambroise Pare´, Boulogne, 92100 France; Consultation multidisciplinaire Marfan [G.J.], Hoˆpital Bichat, Paris, 75018 France; Centre de Ge´ne´tique [L.F.], CHUDijon, Dijon, 21000 France; Centre d’Investigation Clinique– Epide´miologie-Clinique/essais cliniques [L.F., E.G., C.B., C.B.-K.], CHU Dijon, Dijon, 21000 France; INSERM, U827 [G.C.-B., M.C.], Universite´ Montpellier, Montpellier, 34000 France; Department of Cardiological Sciences [A.H.C.], St Georges Hospital, London SW17 0RE, United Kingdom; Molecular Diagnostic Division [E.A.], IRCCS Foundation San Matteo Hospital, Pavia, 27100 Italy; Marfan Research Group and Department of Clinical Genetics [L.C.A.], Children’s Hospital at Westmead, New South Wales 2145, Australia; Department of Genetics and Pediatrics [U.F.], Stanford University Medical Center, Stanford, California 94305; Center for Human Genetics and Laboratory Medicine [K.M.], Martinsried, 82152 Germany; Institut fu¨r Humangenetik [M.A.-K.], Hannover Medical School, Hannover, 30625 Germany; Center for Medical Genetics [A.D.P.], Ghent University Hospital, Ghent, 9000 Belgium; Service de Cardiologie Pediatrique [D.B.], Hoˆpital Necker-Enfants-Malades, Paris, 75015 France ABSTRACT: Marfan syndrome (MFS) is an autosomal dominant along the entire FBN1 gene. MFS is notable for its variability connective tissue disorder. Diagnostic criteria of neonatal MFS in age of onset, tissue distribution, and severity of clinical (nMFS), the most severe form, are still debated. The aim of our study manifestations. neonatal Marfan syndrome (nMFS) is consid- was to search for clinical and molecular prognostic factors that could ered the most severe end of the spectrum of type I fibrilli- be associated with length of survival. Probands ascertained via the nopathies, but diagnostic criteria are still debated. Indeed, framework of the Universal Marfan database-FBN1, diagnosed be- Booms et al. (4) proposed to reserve the term of nMFS for fore the age of 1 y and presenting with cardiovascular features (aortic root dilatation or valvular insufficiency) were included in this study. patients diagnosed at birth or within the first 3 mo of life, Clinical and molecular data were correlated to survival. Among the presenting with pronounced atrioventricular valve dysfunc- 60 individuals, 38 had died, 82% died before the age of 1 y, mostly tion, with death often occurring within the first year of life because of congestive heart failure. Three probands reached adult- because of congestive heart failure. Pulmonary emphysema, hood. Valvular insufficiencies and diaphragmatic hernia were predic- joint contractures, crumpled ears, and loose skin are often tive of shorter life expectancy. Two FBN1 mutations were found associated. They also suggested, like others, that all mutations outside of the exon 24–32 region (in exons 4 and 21). Mutations in causing nMFS cluster in a specific region between exons 24 exons 25–26 were overrepresented and were associated with shorter and 32 (4–6). According to the most recent comment on the ϭ survival (p 0.03). We report the largest genotyped series of subject by Hennekam (7), children with nMFS show severe probands with MFS diagnosed before1yoflife. In this population, mitral and/or tricuspid valvular insufficiency and infantile factors significantly associated with shorter survival are presence of pulmonary emphysema, in addition to the common symptoms valvular insufficiencies or diaphragmatic hernia in addition to a mutation in exons 25 or 26. (Pediatr Res 69: 265–270, 2011) of ectopia lentis, arachnodactyly, joint contractures, and loose skin. Death may occur within the first2yoflife from arfan syndrome (MFS) is an autosomal dominant con- congestive heart failure (7). Life expectancy seems to be the M nective tissue disorder (MIM 154700), the skeletal central issue when managing a patient with early diagnosed features of which were first described by Marfan (1) in 1896. MFS with cardiovascular involvement. To search for prognos- The cardinal features of MFS involve the cardiovascular, tic factors associated with early death, we studied the clinical ocular, and skeletal systems. The skin, lung, and dura may and molecular features of 60 probands carrying mutations in also be involved (2). The prevalence of MFS has been esti- the FBN1 gene and with cardiovascular involvement before mated at 2–3 per 10,000 of the population, and ϳ25% of cases the age of 1 y. are sporadic (3). Mutations in the gene encoding fibrillin-1, FBN1, are known to cause MFS and are widely distributed METHODS Patients. Patients were ascertained through the Universal Marfan data- base-FBN1 (UMD-FBN1; http://www.umd.be) (8), which collects molecular Received May 12, 2010; accepted October 14, 2010. data of patients carrying an FBN1 mutation from 38 countries in five Correspondence: Chantal Stheneur, M.D., Ph.D., Service de pe´diatrie, Hoˆpital A. Pare´, continents and registered between 1995 and 2008 and patients with a patho- 9, Avenue Charles de Gaulle, 92100 Boulogne, France; e-mail: chantal.stheneur@apr. genic FBN1 mutation unpublished were included (9,10). Inclusion criteria aphp.fr Supported by a Grant from the French Ministry of Health (PHRC 2004), GIS maladies rares 2004, Bourse de la Socie´te´ Franc¸aise de Cardiologie, Fe´de´ration Franc¸aise de Cardiologie 2005, Assistance Publique Hoˆpitaux de Paris (CIRC 2007), Abbreviations: IQR, interquartile ratio; MFS, Marfan syndrome; nMFS, and ANR-05-PCOD-014. neonatal MFS 265 266 STHENEUR ET AL. were as follows: i) clinical features allowing a diagnosis of MFS or type I fibrillinopathy in a child before the age of 1 y and ii) presence of cardiovas- cular manifestations including mitral and/or tricuspid valvular insufficiency and/or aortic root dilatation. These criteria were designed to exclude children with some skeletal features of the MFS spectrum but without cardiovascular involvement that could be diagnosed early based on a positive family history. They were also designed to exclude children with clinical features of MFS but mutated in an other gene such as TGFBR1 or TGFBR2 and to permit molecular description of the series. Sixty children diagnosed as MFS before the age of 1 y were identified, designated as nMFS or not by the clinician. Fifty-three of the probands were part of the 320 children described by Faivre et al. (11), whose study was designed for another purpose, and the remaining patients were issued from personal observations or recent publications. Informed consent has been obtained by each clinician. The required clinical information included a range of qualitative and quantitative clinical parameters, among them cardiovascu- lar, ophthalmological, skeletal, skin, and lung manifestations. The age and cause of death or the age at last follow-up and the characteristics of FBN1 mutations were also collected. Patients still alive at last follow-up were designated as “survivors.” Statistical analysis. For descriptive purposes, time-to-event analysis tech- niques were used for survival analyses, and calculation of cumulative prob- ability of a clinical feature when the age at diagnosis was collected. Subjects for whom the age at diagnosis of a specific manifestation was not available were excluded from these analyses. Subjects who did not manifest the feature during the follow-up course were censored at their last follow-up. The baseline date (time zero) was the date of birth. In particular, the Kaplan-Meier method (12) was used to estimate the cumulative probabilities of clinical manifestations of the disease. To search for prognostic factors associated with shorter survival, compar- ison of prevalence of different clinical features was made between the group Figure 1. Kaplan-Meier analysis for survival in patients diagnosed as MFS of patients deceased before the age of 1 y and the group of patients alive at or type 1 fibrillinopathy before the age of 1 y. (A) Overall survival (solid line): this age. Only clinical features present before the age of 1 y were considered. 50% of patients were alive at 4 mo, IQR ϭ 2:66. Area between dashed lines Only patients with available follow-up beyond the age of 1 y were included show pointwise confidence bands (95%). (B) Survival in patients with a ␹2 in the analysis. The or Fisher exact test were used. mutation in FBN1 exons 25–26 (dashed line) vs patients with a mutation in Genotype-phenotype correlation analyses were difficult because of the other exons (solid line): 50% of patients with mutation within exons 25–26 small sample size. It was not possible to compare the type of mutations because the large majority of mutation was private missense mutations. We were alive at 3 mo, whereas 50% of patients with mutation located in other questioned whether the substitution of a cysteine residue was more likely to exons were alive at 12 mo. have phenotypic consequences than mutations affecting another amino acid. Because of the small sample size, it was not possible to compare the phenotypic data for each exon of the region with the others. Therefore, we insufficiencies. Notably, seven survivors (32%) have had a evaluated whether the phenotypic consequences of a mutation in the exons preferentially involved (exons 25 and 26) were different to the consequences valvular surgery. of mutations in the other exons. Differences among the different types of Clinical features of the overall study population are sum- mutation groups were tested using the nonparametric log-rank test.
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